CONSPECTUSBy generating structural complexity in a single step from three or more reactants, multicomponent reactions (MCRs) make it possible to synthesize target compounds with greater efficiency and atom economy. The history of such reactions can be traced to the mid-nineteenth century when Strecker first produced α-aminonitriles from the condensation of aldehydes with ammonia and hydrogen cyanide.Recently, academic chemists have renewed their interest in MCRs. In part, the pharmaceutical industry has fueled this resurgence because of the growing need to assemble libraries of structurally complex substances for evaluation as lead compounds in drug discovery and development programs. The application of MCRs to that increasingly important objective remains limited by the relatively small number of such reactions that can be broadly applied to prepare biologically relevant or naturalproduct-like molecular frameworks.We were interested in applying logic-based approaches, such as our single reactant replacement (SRR) approach, as a way both to improve known MCRs and design new multiple-component routes to bioactive structures. This Account provides several examples that illustrate the use of SRR with known MCRs as starting points for synthetic innovation in this area.As part of our working hypothesis, we initially explored strategies for engineering improvements into known MCRs, either by increasing the dimensionality-i.e. changing an n-component to an (n +1)-component reaction-or broadening the scope of useful input structures, or both. By exhaustively applying retrosynthetic analysis to the cognate MCR to identify and exploit alternative entry points into the overall reaction manifold, we have devised several such re-engineered MCRs. Serendipitous findings have also augmented the yield of useful developments from our logic-inspired approach. In some cases, we have identified surprising links between different compound families that provide useful new entry points for chemical library synthesis. In other cases, the same re-engineering logic made it possible (sometimes in unexpected ways) to transform certain non-elementary twocomponent reactions into higher order MCRs.While logic may also inspire the search for new MCRs, the design process requires added chemical creativity, which cannot be reduced to a simple formula. The long-term goal of our research is to expand the useful repertoire of such reactions, which are important as complexity-generating tools in both combinatorial and diversity-oriented synthesis. MCRs represent the cornerstones of both combinatorial chemistry and diversity-oriented synthesis, and thus have played a central role in the development of modern synthetic methodology for pharmaceutical and drug discovery research. 3 Used in conjunction with target-oriented synthesis, combinatorial chemistry approaches can be employed to introduce or broaden structural variations in a lead compound of interest. Diversity-oriented synthesis is helpful in exploring large areas of chemical structure space in ...

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